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Preparation method of linezolid intermediate

A technology of linezolid and intermediates is applied in the field of preparation of linezolid intermediates and achieves the effects of simple preparation steps, low price and stable sources

Active Publication Date: 2021-03-09
泰州申合泰尔生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The object of the present invention is to provide a kind of preparation method of linezolid intermediate, to solve the problem raised in the above-mentioned background technology

Method used

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  • Preparation method of linezolid intermediate

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Experimental program
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Effect test

Embodiment 1

[0034] The preparation steps of the intermediate N-(3-phthalimido-2-(S)-hydroxypropyl)-3-fluoro-4-(morpholinyl)aniline (I) of linezolid are as follows:

[0035] Raw material preparation: N,N-dimethylacetamide is the dipolar solvent of amide, and sodium bromide is selected as the reaction accelerator;

[0036] (II):(III) The molar ratio is 2:1.

[0037] (1) In a 250ml reaction flask, dissolve 4.0g (II) in 30ml of N,N-dimethylacetamide solvent, add 2.4g (III) and 1.0g sodium bromide, stir for 20min, and heat up to Under the condition of 100°C, react for 20 hours to obtain the reaction liquid;

[0038] (2) the reaction solution that step (1) is obtained is cooled to room temperature; Add 50ml dichloromethane and 50ml water, stir and separate liquids, add 50ml water in the organic phase, wash 3 times, the organic phase is dried with anhydrous magnesium sulfate, The crude product was obtained by concentration, and the crude product was separated by column chromatography to obtain...

Embodiment 2

[0040] The preparation steps of the intermediate N-(3-phthalimido-2-(S)-hydroxypropyl)-3-fluoro-4-(morpholinyl)aniline (I) of linezolid are as follows:

[0041]Raw material preparation: N,N-dimethylacetamide is the dipolar solvent of amide, and sodium bromide is selected as the reaction accelerator;

[0042] (II):(III) The molar ratio is 1.77:1.

[0043] (1) In a 250ml reaction flask, dissolve 3.5g (II) in 30ml of N,N-dimethylacetamide solvent, add 2.4g (III) and 1.5g sodium bromide, stir for 20min, and heat up to Under the condition of 100°C, react for 20 hours to obtain the reaction solution;

[0044] (2) the reaction solution that step (1) is obtained is cooled to room temperature; Add 50ml dichloromethane and 50ml water, stir and separate liquids, add 50ml water in the organic phase, wash 3 times, the organic phase is dried with anhydrous magnesium sulfate, The crude product was obtained by concentration, and the crude product was separated by column chromatography to ob...

Embodiment 3

[0046] The preparation steps of the intermediate N-(3-phthalimido-2-(S)-hydroxypropyl)-3-fluoro-4-(morpholinyl)aniline (I) of linezolid are as follows:

[0047] Raw material preparation: N,N-dimethylacetamide is the amide dipole solvent, and tetrabutylammonium bromide is selected as the reaction accelerator;

[0048] (II):(III) The molar ratio is 1.83:1.

[0049] (1) In a 250ml reaction flask, dissolve 3.6g (II) in 30ml of N,N-dimethylacetamide solvent, add 2.4g (III) and 1.5g tetrabutylammonium bromide, and stir for 25min , heated up to 120°C, and reacted for 21 hours to obtain a reaction liquid;

[0050] (2) the reaction solution that step (1) is obtained is cooled to room temperature; Add 50ml dichloromethane and 50ml water, stir and separate liquids, add 50ml water in the organic phase, wash 3 times, the organic phase is dried with anhydrous magnesium sulfate, The crude product was obtained by concentration, and the crude product was separated by column chromatography to...

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Abstract

The invention discloses a preparation method of a linezolid intermediate. The preparation method comprises the following steps: by taking 3-fluoro-4- (4-morpholinyl) -aniline and 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone as main raw materials, carrying out substitution reaction in an amide dipole solvent at the temperature of 90-150 DEG C to obtain N- (3-phthalimido-2- (S) -hydroxypropyl) -3-fluoro-4- (morpholinyl) aniline which is an important intermediate for synthesizing the antibiotic linezolid. The preparation steps of the intermediate are simple, dangerous reagents such as butyl lithium, sodium azide, chloroformate and methylsulfonyl chloride which are inflammable, explosive and highly toxic in the conventional process are not used in the preparation process, and the safety is high; the main raw materials of 3-fluoro-4- (4-morpholinyl) -aniline and 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone are stable in source and low in cost, the used amidedipole solvent is easy to recycle, and the pollution to the environment can be reduced.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a linezolid intermediate. Background technique [0002] Linezolid is the first new type of oxazolidinone antibacterial drug used in clinical practice, and it shows high antibacterial activity against various Gram-positive cocci in vivo and in vitro. Linezolid is a bacterial protein synthesis inhibitor that acts on the bacterial 50S ribosomal subunit to terminate bacterial protein synthesis. The site and mode of action of linezolid are unique, and it is not easy to cross-resistance with other antibacterial drugs that inhibit protein synthesis, and it is not easy to induce drug resistance in vitro. It is mainly used for the treatment of bacteremia caused by vancomycin-resistant enterococci (VRE), pneumonia and comprehensive skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and bacteremia caused by penicillin-resistant Stre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48C07D413/06
CPCC07D209/48C07D413/06C07B2200/07
Inventor 孙炳峰孙炳峻孔德剑
Owner 泰州申合泰尔生物医药有限公司